Kinga Hadzsiev

Hyponatremia and Sensorineural Hearing Loss in Preterm Infants

In a case-control study the role of hyponatremia in the hearing loss of preterm infants was investigated. One hundred and sixty-four premature infants treated at the neonatal intensive care unit were screened with transient evoked otoacoustic emission (TEAOE). In 32 infants TEAOE results indicated the need for further investigations. Auditory brainstem response was performed and 22 of 32 cases had bilateral hearing impairment (HI). The birth weight and gestational age in the HI group were 1,425 ± 528 g and 30.4 ± 3.7 weeks. The matched control group consisted of 25 infants with a mean birth weight and gestational age of 1,410 ± 280 g and 31.1 ± 2.1 weeks. Significant differences were found between the HI and control groups: Apgar score (p < 0.05), pH value (p < 0.01) and pO2 level (p < 0.05) were lower; the total dose of aminoglycosides (p < 0.01), furosemide usage (p < 0.01), the maximum pCO2 level (p < 0.01), incubator stay (p < 0.05) and hyponatremia (p < 0.01) were higher, and the duration of hyponatremia (p < 0.05) was longer in the HI group. Multivariate logistic regression revealed that aminoglycoside treatment and hyponatremia were the two most significant factors in the development of hearing impairment. These results suggest that hyponatraemia is an additional risk factor for hearing loss in preterm infants.

Congenital disorder of glycosylation type Ix: review of clinical spectrum and diagnostic steps.

SummaryCongenital disorder of glycosylation type I (CDG I) represent a rapidly growing group of inherited multisystem disorders with 13 genetically established subtypes (CDG Ia to CDG Im), and a high number of biochemically unresolved cases (CDG Ix). Further diagnostic effort and prognosis counselling are very challenging in these children. In the current study, we reviewed the clinical records of 10 CDG Ix patients and compared the data with 13 CDG Ix patients published in the literature in search for specific symptoms to create clinical subgroups. The most frequent findings were rather nonspecific, including developmental delay and axial hypotonia. Several features were found that are uncommon in CDG syndrome, such as elevated creatine kinase or arthrogryposis. Distinct ophthalmological abnormalities were observed including optic nerve atrophy, cataract and glaucoma. Two subgroups could be established: one with a pure neurological presentation and the other with a neurological-multivisceral form. The first group had a significantly better prognosis. The unique presentation of microcephaly, seizures, ascites, hepatomegaly, nephrotic syndrome and severe developmental delay was observed in one child diagnosed with CDG Ik. Establishing clinical subgroups and increasing the number of patients within the subgroups may lead the way towards the genetic defect in children with a so far unsolved type of the congenital disorders of glycosylation. Raising awareness for less common, non-CDG specific clinical features such as congenital joint contractures, movement disorders or ophthalmological anomalies will encourage clinicians to think of CDG in its more unusual presentation. Clinical grouping also helps to determine the prognosis and provide better counselling for the families.

Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway

Various syndromes of the Ras-mitogen-activated protein kinase (MAPK) pathway, including the Noonan, Cardio-Facio-Cutaneous, LEOPARD and Costello syndromes, share the common features of craniofacial dysmorphisms, heart defect and short stature. In a subgroup of patients, severe muscle hypotonia, central nervous system involvement and failure to thrive occur as well. In this study we report on five children diagnosed initially with classic metabolic and clinical symptoms of an oxidative phosphorylation disorder. Later in the course of the disease, the children presented with characteristic features of Ras-MAPK pathway-related syndromes, leading to the reevaluation of the initial diagnosis. In the five patients, in addition to the oxidative phosphorylation disorder, disease-causing mutations were detected in the Ras-MAPK pathway. Three of the patients also carried a second, mitochondrial genetic alteration, which was asymptomatically present in their healthy relatives. Did we miss the correct diagnosis in the first place or is mitochondrial dysfunction directly related to Ras-MAPK pathway defects? The Ras-MAPK pathway is known to have various targets, including proteins in the mitochondrial membrane influencing mitochondrial morphology and dynamics. Prospective screening of 18 patients with various Ras-MAPK pathway defects detected biochemical signs of disturbed oxidative phosphorylation in three additional children. We concluded that only a specific, metabolically vulnerable sub-population of patients with Ras-MAPK pathway mutations presents with mitochondrial dysfunction and a more severe, early-onset disease. We postulate that patients with Ras-MAPK mutations have an increased susceptibility, but a second metabolic hit is needed to cause the clinical manifestation of mitochondrial dysfunction.

Phenotypic Variants of the Deafness-Associated Mitochondrial DNA A7445G Mutation

A number of nuclear and mitochondrial mutations have been implicated in non-syndromic hearing loss. Among them, various mutations of mitochondrial Ser(UCN)-tRNA and 12S rRNA genes have been found to be associated with deafness; the A7445G mitochondrial DNA (mtDNA) in this group is unique, simultaneously affecting two different mitochondrial genes, encoding the Ser(UCN)-tRNA and the first subunit of cytochrome oxidase. Besides the hearing loss, it is mainly associated with palmoplantar keratoderma, though; different phenotypic associations have been reported. The current paper reviews the available PubMed reports on the A7445G mtDNA mutation, with special attention to the phenotypic variations. Further, a Hungarian family with the A7445G mutation is reported, in which analysis of both the affected and the non-affected members revealed the mutation in both homo- and heteroplasmic forms, independently of the hearing status of the subjects, a phenomenon previously not reported in other pedigrees. The female lineage represented a rare variant of the U4b haplogroup.

Exome sequencing identifies Laing distal myopathy MYH7 mutation in a Roma family previously diagnosed with distal neuronopathy

We describe a Hungarian Roma family, originally investigated for autosomal dominant distal muscular atrophy. The mother started toe walking at 3 years and lost ambulation at age 27. Her three daughters presented with early steppage gait and showed variable progression. Muscle biopsies were nonspecific showing myogenic lesions in the mother and lesions resembling neurogenic atrophy in the two siblings. To identify the causative abnormality whole exome sequencing was performed in two affected girls and their unaffected father, unexpectedly revealing the MYH7 mutation c.4849_4851delAAG (p.K1617del) in both girls, reported to be causative for Laing distal myopathy. Sanger sequencing confirmed the mutation in the affected mother and third affected daughter. In line with variable severity in Laing distal myopathy our patients presented a more severe phenotype. Our case is the first demonstration of Laing distal myopathy in the Roma and the successful use of whole exome sequencing in obtaining a definitive diagnosis in ambiguous cases.

Mutations of the apolipoprotein A5 gene with inherited hypertriglyceridaemia: Review of the current literature

Apoliporotein A5 (APOA5), a member of the apolipoprotein family, plays a key regulatory role in triglyceride (TG) metabolism. Even though the exact biochemical background of its mechanism is not yet fully understood, diseases associated with this particular gene highlighted its key role in the metabolism of triglycerides in humans. Naturally occurring functional variants of the gene and their natural major haplotypes are known to associate with moderately elevated triglyceride levels, and are also known to confer risk or protection for major polygenic diseases, like coronary heart disease, stroke, or metabolic syndrome. On the other hand, case reports and even robust resequencing studies verified APOA5 mutations as underlying genetic defects behind extreme hypertriglyceridemic phenotype. Soon after the recognition of the first cases, there were indications which suggest the existence of less frequent genetic variants which, in combination with the common allelic variants of the gene, can define haplotypes that are associated with substantial triglyceride level increase. In addition, it became evident, that there are rare mutations of the APOA5 gene which can be associated with specific complex phenotypes and different types of hyperlipoproteinemia, which includes extremely high triglyceride levels with multiple organ pathology. These rare mutations may cause inheritable hypertriglyceridemia, but they presented at a low frequency and could not be captured by standard genotyping array screenings. The identification of new mutations still relies on the direct sequencing of APOA5 gene of patients with hypertriglyceridemia with an unusual pattern, individually or in huge resequencing studies.

A novel IL2RG mutation associated with maternal T lymphocyte engraftment in a patient with severe combined immunodeficiency

AbstractSevere combined immunodeficiency (SCID) represents a genetically heterogeneous group of primary immunodeficiency disorders. Irrespective of the genetic defect, patients with SCID may be engrafted with transplacentally derived maternal T-lymphocytes that in a subset of cases may be responsive to phytohemagglutinin. Here, we present, from a genetic perspective, an SCID patient who not only harbored a novel mutation in the gene encoding the common γ chain (γc) of the IL-2 receptor (IL2RG), but also carried reactive maternal T lymphocytes that produced a karyotype that was initially perplexing.

Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations.

Rett syndrome (RTT) is characterized by a relatively specific clinical phenotype. We screened 152 individuals with RTT phenotype. A total of 22 different known MECP2 mutations were identified in 42 subjects (27.6%). Of the 22 mutations, we identified 7 (31.8%) frameshift-causing deletions, 4 (18.2%) nonsense, 10 (45.5%) missense mutations and one insertion (4.5%). The most frequent pathologic changes were: p.Thr158Met (14.2%) and p.Arg133Cys (11.9%) missense, and p.Arg255Stop (9.5%) and p.Arg294Stop (9.5%) nonsense mutations. We also detected the c.925C>T (p.Arg309Trp) mutation in an affected patient, whose role in RTT pathogenesis is still unknown. Patients without detectable MECP2 defects were screened for mutations of cyclin-dependent kinase-like 5 (CDKL5) gene, responsible for the early-onset variant of RTT. We discovered two novel mutations: c.607G>T resulting in a termination codon at aa203, disrupting the catalytic domain, and c.1708G>T leading to a stop at aa570 of the C terminus. Both patients with CDKL5 mutation presented therapy-resistant epilepsy and a phenotype fitting with the diagnosis of early-onset variant of RTT. No FOXG1 mutation was detected in any of the remaining patients. A total of 110 (72.5%) patients remained without molecular genetic diagnosis that necessitates further search for novel gene mutations in this phenotype. Our results also suggest the need of screening for CDKL5 mutations in patients with Rett phenotype tested negative for MECP2 mutations.

The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome.

Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X‐inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base‐pair substitution affecting Arg309 at the C‐terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X‐inactivation patterns in target tissues.

Increased prevalence of functional minor allele variants of drug metabolizing CYP2B6 and CYP2D6 genes in Roma population samples

BACKGROUND Cytochrome P450 2B6 and 2D6 are important enzymes in human drug metabolism. These phase I enzymes are known to contribute the biotransformation of clinically important pharmaceuticals, including antidepressants, anticancer and anxiolytic drugs. The aim of this work was to determine the pharmacogenetic profile of CYP2B6 and CYP2D6 in Roma and Hungarian population samples. METHODS A study population of 426 healthy Roma and 431 healthy Hungarian subjects were characterized for CYP2B6 c.516G>T, CYP2D6 c.100C>T and c.1846G>A polymorphisms using predesigned TaqMan Drug Metabolism Genotyping Real Time-PCR assays. RESULTS We found significant differences in the presence of CYP2B6 c.516G>T (p<0.001), CYP2D6 c.100C>T (p=0.003) and c.1846G>A (p=0.022) between Hungarian and Roma population. The 516T allele frequency was 33.6% in the Roma group, 21.4% in Hungarians, whereas the minor CYP2D6 100T allele was present in 26.6% in Romas and 20.5% in Hungarians. The 1864A allele frequency was 22.5% in Roma and 18.1% in Hungarian samples. A significant increase was found in genotype frequencies for homozygous minor allele carrier Roma participants compared to Hungarians for CYP2B6 516TT and CYP2D6 100TT. The following CYP2D6 genotypes were identified in Roma samples: *1/*1 (55.4%), *1/*4 (2.1%), *1/*10 (3.1%), *4/*10 (38.7%), *10/*10 (0.7%). CONCLUSION Our results demonstrate an increased minor allele frequency for CYP2B6 and CYP2D6 polymorphisms in Roma samples that implies clinical significance in this ethnic group.